CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS
铂类抗癌药物的化学和生物学
基本信息
- 批准号:7955152
- 负责人:
- 金额:$ 0.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:Antineoplastic AgentsBase PairingBiologyChemistryCisplatinColorectal CancerComplexComputer Retrieval of Information on Scientific Projects DatabaseDNADNA AdductsDNA StructureDataFundingGenetic TranscriptionGrantInstitutionLeftLesionMajor GrooveModelingMolecular ConformationMolecular Mechanisms of ActionMusPlatinumPlatinum CompoundsProteinsResearchResearch PersonnelResourcesSideSiteSourceStructural ModelsStructure-Activity RelationshipUnited States National Institutes of HealthWorkX ray diffraction analysisX-Ray Diffractionadductantitumor agentcrosslinkcytotoxicityin vivointerestpyridinerepairedstructural biologytumor
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The platinum compound cis-[Pt(NH3)2(pyridine)Cl]Cl has previously demonstrated potent cytotoxicity in a screen against in vivo murine tumor models. This result is of particular interest because this compound forms only monofunctional adducts with DNA, and thus does not follow the classic structure-activity relationship for platinum anti-tumor agents that requires two leaving groups to be present in a cis conformation. Recent data has shown this compound may be recognized by cellular repair proteins and block transcription in a manner that is unique to monofunctional platinum compounds, but similar to cisplatin and other bifunctional platinum compounds. It is therefore desirable to obtain a detailed structural model of this platinum-DNA adduct, which may help to explain the unexpected activity of the complex. We have recently crystallized a DNA dodecamer duplex containing a single {Pt(NH3)2(pyridine)}-dG adduct, and collected X-ray diffraction data to 2.17 ¿. The global structure of the DNA is quite different from that of DNA containing a platinum intrastrand d(GpG) cross-link. The latter platinated duplex is bent by ~40¿ towards the major groove at the site of the cross-link, yet the monofunctional platinumdG lesion causes no significant distortion of the double helix. Like the cisplatin intrastrand cross-link, however, the monofunctional adduct creates a distorted base pair step to the 5' side of the platinum site that may be correlated to antitumor activity. These data allow us to reevaluate the structure-activity relationship of platinum anticancer agents to include monofunctional, "non-classical" platinum compounds, and to use this evidence to work towards elucidating the molecular mechanism of action of a unique platinum complex that may be able to be used in treatment of colorectal cancer.
这个子项目是许多研究子项目中的一个
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
铂化合物cis-[Pt(NH3)2(吡啶)Cl]Cl先前已在针对体内鼠肿瘤模型的筛选中证明了有效的细胞毒性。该结果是特别令人感兴趣的,因为该化合物仅与DNA形成单官能加合物,因此不遵循铂抗肿瘤剂的经典结构-活性关系,其需要两个离去基团以顺式构象存在。 最近的数据表明,这种化合物可以被细胞修复蛋白识别,并以单功能铂化合物特有的方式阻断转录,但与顺铂和其他双功能铂化合物相似。 因此,希望获得这种铂-DNA加合物的详细结构模型,这可能有助于解释复合物的意外活性。 我们最近结晶的DNA十二聚体双链体含有一个单一的{Pt(NH 3)2(吡啶)}-dG加合物,并收集X射线衍射数据到2.17。DNA的整体结构与含有铂链内d(GpG)交联的DNA完全不同。后一种含铂双链体在交联位点处向大沟弯曲约40 <$s,而单官能铂双链体在交联位点处向大沟弯曲约40 <$s。dG损伤不引起双螺旋的显著变形。然而,与顺铂链内交联一样,单官能加合物在铂位点的5'侧产生扭曲的碱基对台阶,这可能与抗肿瘤活性相关。这些数据使我们能够重新评估铂类抗癌药物的结构-活性关系,包括单功能的“非经典”铂化合物,并利用这些证据来阐明一种独特的铂络合物的分子作用机制,这种铂络合物可能用于治疗结直肠癌。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stephen J. Lippard其他文献
X-ray structure of a dodecamer duplex containing the major cisplatin d(GpG) intrastrand cross-link
- DOI:
10.1016/0162-0134(95)97300-f - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Patricia M. Takahara;Amy C. Rosenzweig;Christin A. Frederick;Stephen J. Lippard - 通讯作者:
Stephen J. Lippard
Frank Albert Cotton (1930–2007)
弗兰克·艾伯特·科顿(1930 年至 2007 年)
- DOI:
10.1038/446626a - 发表时间:
2007-04-04 - 期刊:
- 影响因子:48.500
- 作者:
Stephen J. Lippard - 通讯作者:
Stephen J. Lippard
High resolution crystal structures of the hydroxylase protein of methane monooxygenase
- DOI:
10.1016/0162-0134(95)97479-a - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Amy C. Rosenzweig;Pär Nordlund;Stephen J. Lippard;Christin A. Frederick - 通讯作者:
Christin A. Frederick
Conjugués de nanoparticule de polynucléotide polyvalente en tant que véhicules de distribution pour un agent chimiothérapique
多核苷酸多价纳米粒子结合物与化学药物分配载体
- DOI:
- 发表时间:
2010 - 期刊:
- 影响因子:0
- 作者:
Chad A. Mirkin;David A. Giljohann;W. Daniel;Stephen J. Lippard;Shanta Dhar - 通讯作者:
Shanta Dhar
Structural, mechanistic, and model studies for methane monooxygenase
- DOI:
10.1016/0162-0134(95)97192-s - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Stephen J. Lippard - 通讯作者:
Stephen J. Lippard
Stephen J. Lippard的其他文献
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{{ truncateString('Stephen J. Lippard', 18)}}的其他基金
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
8362193 - 财政年份:2011
- 资助金额:
$ 0.22万 - 项目类别:
INVESTIGATIONS OF CISPLATIN-DNA CROSS-LINKS ON NUCLEOSOME CORE PARTICLES
核小体核心颗粒上顺铂-DNA 交联的研究
- 批准号:
8169250 - 财政年份:2010
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
8170154 - 财政年份:2010
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF MULTICOMPONENT BACTERIAL MONOOXYGENASES
多组分细菌单加氧酶的结构研究
- 批准号:
8169251 - 财政年份:2010
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7954158 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
Nonheme Diiron Centers and the Biological Oxidation of Hydrocarbons
非血红素二铁中心和碳氢化合物的生物氧化
- 批准号:
7923548 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF MULTICOMPONENT BACTERIAL MONOOXYGENASES
多组分细菌单加氧酶的结构研究
- 批准号:
7955153 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7954496 - 财政年份:2009
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7721732 - 财政年份:2008
- 资助金额:
$ 0.22万 - 项目类别:
STRUCTURAL STUDIES OF BACTERIAL MULTICOMPONENT MONOOXYGENASES
细菌多组分单加氧酶的结构研究
- 批准号:
7597911 - 财政年份:2007
- 资助金额:
$ 0.22万 - 项目类别:
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